A property of HIV-1 and other lentiviruses is their ability to infect non-dividing cells, such as primary macrophages and dendritic cells, as well as growth-arrested cells. This requires nuclear import of virus pre-integration complex (PIC) along with the virus genome, across the intact nuclear membrane of the non- dividing cell. Recent studies have also correlated nuclear import with infection of activated primary CD4+ T lymphocytes. Nuclear import is dependent on association of the PIC with cellular karyopherin alpha, a nuclear localization sequence (NLS)-binding protein. A component of PIC, matrix protein (MA), contains the NLS which mediates association of PIC with karyopherin alpha. The resulting protein-protein interaction represents a molecular target for a novel approach to HIV-1 drug development. Agents that disrupt this interaction by targeting specific sequences on either protein will inhibit nuclear import of the PIC. The primary objectives of this study are to identify small molecule inhibitors targeting MA sequences critical to PIC- karyopherin alpha binding, and characterize in vitro their antiviral properties in dividing and non-dividing target cell cultures in order to select high potency non-toxic pre-clinical drug candidates. Successful candidates represent potential therapies for treatment of HIV-1 infection that are significantly different from the current anti-viral approaches targeting viral enzymes. PROPOSED COMMERCIAL APPLICATION Identified novel high potency anti-HIV-1 therapeutics will be applied to existing HAART therapy to broaden the spectrum of the antiviral targets. Activity of these novel compounds will not be affected by existing mutations to current established therapies.